The ontogeny of drug metabolizing enzymes and transporters in the rat.
Knowledge of the ontogeny of the various systems involved in distribution and elimination of drugs is important for adequate interpretation of the findings during safety studies in juvenile animals. The present study was designed to collect information on plasma concentrations of total protein and albumin, enzyme activity and mRNA expression of cytochrome P450 isoenzymes (CYP1A1/2, CYP2B1/2, CYP2E1, CYP3A1/2, and CYP4A1), carboxylesterase and thyroxin glucuronidation (T4-GT) activity in liver microsomes, and mRNA expression of transporters (Mdr1a/b, Mrp1-3 and 6, Bsep and Bcrp, Oct1-2, Oat1-3 and Oatp1a4) in liver, kidney and brain tissue during development in Sprague-Dawley rats. Enzyme activities were determined by measuring the metabolism of marker substrates; expression of mRNAs was assessed using RTq-PCR. There were considerable differences in the ontogeny of the individual cytochrome P450 isoenzymes. In addition, ontogeny patterns of enzyme activity did not always parallel ontogeny patterns of mRNA expression. Ontogeny of the transporters depended on the transporter and the organ studied. Changes in mRNA expression of the various transporters during development are likely to result in altered elimination and/or tissue distribution of substrates, with concomitant changes in hepatic metabolism, renal excretion and passage through the blood-brain barrier. Consideration of the ontogeny of metabolizing enzymes and transporters may improve the design and interpretation of results of toxicity studies in juvenile animals.
de Zwart
Loeckie
L
Global Preclinical Development, Johnson and Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium. ldzwart@its.jnj.com
Scholten
Martijn
M
Monbaliu
Johan G
JG
Annaert
Pieter P
PP
Van Houdt
Jos M
JM
Van den Wyngaert
Ilse
I
De Schaepdrijver
Luc M
LM
Bailey
Graham P
GP
Coogan
Timothy P
TP
Coussement
Werner C
WC
Mannens
Geert S
GS
D018528:ATP-Binding Cassette Transporters / Q000032:analysis* / Q000235:genetics; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001798:Blood Proteins / Q000032:analysis*; D050482:Catecholamine Plasma Membrane Transport Proteins / Q000032:analysis / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis* / Q000235:genetics; D005260:Female; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D027362:Organic Anion Transport Protein 1 / Q000032:analysis / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000032:analysis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D018528:ATP-Binding Cassette Transporters; D001798:Blood Proteins; D050482:Catecholamine Plasma Membrane Transport Proteins; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C493212:Slc22a1 protein, rat; C421043:Slc22a6 protein, rat; C088800:Slc22a7 protein, rat; D003577:Cytochrome P-450 Enzyme System